The broad long term objectives of this proposal are to understand the interactions between the humoral clotting factors and components of the vessel wall including collagen IV, platelets, endothelium and the thrombin- thrombomodulin complex on endothelium. Recent evidence shows that collagen IV specifically binds factor IV, but the functional consequence of this interaction is unknown, but will be sought during this grant period. Furthermore, collagen IV is an agonist for alpha2beta1 on platelets and triggers an intracellular collagen receptor kinase, whose role in platelet physiology will be explored. The regulatory role of the protein C inhibitor on activated protein C resulting from the action of thrombin- thrombomodulin complex will also be sought. Finally, structure-function studies in factor IV and other clotting factors will be carried out. These studies will be carried out over the next five years and should gretly add to our understanding of the physiology of normal hemostasis as well as the pathological consequences of thrombosis and hemorrhage, both of which contribute to great mortality and morbidity in this country.